Submitted in response to CREG Announcement: Metabolism and Mechanism of Action of Carcinogenic Organohalogen Compounds--Number DCCP-19 as appeared in NIH Guide for Grants and Contracts, Vol. 5, No. 2, April 1, 1976. The chronic occupational exposure of anesthesiologists and chemists to various volatile chemicals may be related to the higher incidence of death from cancer reported in these two groups as compared to other professional men. Most of the gaseous anesthetics and many widely used solvents are classified as organohalogens. Many organohalogens are known or suspected to be hepatotoxins and hepatocarcinogens after bioactivation to chemically reactive inermediates. The objectives of this proposal are to study the bioactivation (metabolism to reactive intermediates) and covalent binding of certain halogenated alkanes and alkenes to tissue macromolecules: DNA, RNA, protein, and lipids. The compounds to be studied are known or suspected carcinogens (carbon tetrachloride, chloroform, trichloroethylene and bromotrichloromethane); gaseous anesthetics (halothane, fluroxene, methoxyflurane, isoflurane and enflurane); and two related compounds (dichloroethylene and methylene chloride). Bioactivation and covalent binding will be studied in vitro using isolated liver, lung or kidney microsomes with endogenously added DNA or in isolated liver cells; and in vivo by extracting DNA, RNA, protein and lipids from various tissues after the administration of 14C-labeled organohalogens. Bioactivation and binding will be studied in various strains of mice, in rats and in hamsters. The effects of pretreatment with general inducers of drug metabolism, more specific inducers of halomethane metabolism (acetone, ethyl alcohol) and depletors of liver glutathione will be determined on the covalent binding of these compounds. Thin layer, column and/or high pressure liquid chromatography will be used to separate the nucleic acid bases, amino acids and lipids and mass spectral analysis will be used to identify the binding species and the tissue adduct to which it is bound.